A large body of epidemiologic evidence has consistently linked reproductive factors to breast cancer risk. Ages at menarche and first pregnancy are parameters in established breast cancer risk models/-1-3. Obesity and hormone replacement therapy also increase postmenopausal breast cancer risk/4. SERMS, such as tamoxifen and raloxifene, not being widely prescribed to reduce breast cancer risk/8. This is due to perceptions about side effects and the inability to identify those women who most benefit from tamoxifen. We and others have shown that postmenopausal levels of serum estrogens are highly correlated with breast cancer risk 9,10. Strategies of estrogen deprivation are increasingly prominent among the various therapeutic hormonal interventions used for hormone receptor positive tumors. In postmenopausal women, adjuvant chemical or surgical oophorectomy may improve survival/11. In postmenopausal women, agents that inhibit aromatase, the critical enzyme in conversion of precursors to estrogen reduce estrogen levels in the circulation, breast tissue, and tumors 12. Currently available aromatase inhibitors are highly selective and substantially reduce circulating estrogen levels without altering other aspects of steroid production 13. They are effective in the treatment of metastatic disease, and a large adjuvant trial is in progress. The goal of this project is to improve breast cancer prevention by translating these observation into clinical practice. In aim one, we will test the hypothesis that by incorporating data on serum estrogen levels and mammographic density from the Nurses' Health Study we can improve current models of individual breast cancer risk. In the second aim, we will develop a novel paradigm for breast cancer prevention among postmenopausal women at increased risk of high levels of circulating estrogens. We will assess whether an aromatase inhibitor is sufficiently well tolerated (by its effects on bone density, menopausal symptoms and blood lipids) to permit further development for chemoprevention. If successful, these studies will contribute to the adoption of quantitative paradigm of breast cancer risk estimation and reduction that more closely parallels the widely accepted models of cholesterol and blood pressure titration that have transformed cardiovascular disease in the US.